Drug abuse is an important public health problem in all human societies. One fast spreading drug has been methamphetamine, known as "ice" in its crystal form. This is an increasingly popular and addictive drug of abuse among adolescents. Exposure is often associated with symptoms of psychosis, indistinguishable from schizophrenia, as well as cognitive impairment. Vulnerable drug users experience persistent psychosis and neuropsychological deficits even after long periods of abstinence. Increased understanding of this drug's mechanism of action may be useful in the public fight against its damaging effects, while also providing insight into the mechanisms of psychosis. We will establish a cohort of 100 adolescent subjects with a history of methamphetamine exposure and a second group of 50 age- and gender-matched healthy adolescents. Our Specific Aims examine the following working hypotheses: 1) that clinical assessment will be able to characterize the variation of intensity and duration of psychotic symptoms with the expectation that the severity of these symptoms will not correlate with cognitive changes, especially memory deficits within our adolescent sample population; 2) that the volumes and metabolism of frontal cortex, striatum, anterior cingulate cortex, and hippocampus, as measured with 3-Tesla MR imaging tools, will be significantly reduced in methamphetamine-exposed adolescents; 3) that strong disturbance of the HPA axis response to psychosocial stress is significantly correlated with the severity of psychotic symptoms, whereas the correlation with cognitive impairment especially memory deficits, will be less significant; 4) that morphological alterations in the mouse cortex striatum and hippocampus in response to methamphetamine are similar to those in humans. From our proposed mouse studies we expect to develop a comprehensive understanding of methamphetamine-induced brain changes because such an understanding cannot readily be obtained from humans. In this way, we utilize the mouse model to investigate functional, microstructural and histochemical effects on the brain under well controlled experimental conditions. We believe these studies will contribute to the overall aims of this award by further delineating how stressors affect emotional and cognitive functions.